Objectives:
To identify the infectious aetiology and clinical features of Acute
Undifferentiated Fever among patients admitted to a teaching hospital
in Pondicherry. Design:
Prospective observational study. Subjects:
270 cases comprising all adult patients (≥18 years) admitted to
the hospital with fever of less than 14 days duration, temperature
≥38ºC upon admission and non-detection of any specific
foci of infection by history, physical examination and routine
investigations. Previously diagnosed cases of known fevers, collagen
vascular disorders, endocrine disorders, malignancies, immunodeficient
states, fever of duration ≥14 days and drug induced fevers were
excluded. Methods: All patients were examined and investigated
according to study protocol after an informed consent to reach final
diagnosis. Results:
38.1% cases were of Scrub Typhus aetiology, 20% cases tested positive
for dengue, 14.1% cases came positive for Enteric fever and Malaria was
found in 5.6% cases, all of P. vivax parasite. There was 1 case of TB,
1 case of candida infection and 1 case of Klebsiella pneumonia. 1 case
tested positive for leptospirosis. Blood pathogens isolated were
Pseudomonas and Enterococci with 1 case each. UTI was a frequent
diagnosis with 7 cases of E. coli, 1 case of Enterococci and 1 case of
Staphylococci. 1 case of HIV was detected. Conclusion: Scrub
typhus was the most common aetiology of Acute Undifferentiated Fever
followed by Dengue and Enteric fever.

Acute undifferentiated fever (AUF) is a common cause of patients
seeking healthcare in India [1, 2]. Unlike fever of unknown origin
(FUO), which has a standard definition, AUF, also known as
“acute febrile illness”, “short febrile
illness”, or “acute fever” lacks an
international consensus definition. Since FUO requires duration of
fever to be longer than three weeks, some authors have defined AUF as
fever that resolves within three weeks. Thus the term AUF is used to
denote fevers that typically do not extend beyond 21 days, and lack
localizable or organ-specific clinical features [3].

AUF poses a diagnostic and therapeutic challenge to the healthcare
workers, particularly in limited resource settings. A number of
viruses, bacteria, protozoa and rickettsia can cause AUF. The
non-specificity of symptoms and signs and lack of availability of
accurate diagnostics not only challenge the diagnosis but often leads
to irrational use of antibiotics and antimalarials. Some fever
syndromes have a more clear localization to skin and soft tissue,
meninges or neural tissue, respiratory tract, or urinary tract. These
syndromes have better developed guidelines for their management. On the
other hand, AUF-syndromes have overlapping aetiologies, which makes
their diagnosis and management challenging [4].

Those AUFs which persist, and total duration of illness becomes longer
than three weeks are classified as FUO. Diagnosis of many aetiologies
of AUF in the tropics can be established with help of simple tests,
such as peripheral smear examination or rapid diagnostic tests (RDTs)
for malaria or dengue [3, 5, 6]. Some other aetiologies need more
sophisticated tests such as ELISA for rickettsial infections, MAT or
ELISA for leptospirosis or PCR based tests for paramyxoviruses [7, 8,
9]. Depending on the nature of available laboratory support, between a
quarter and half of AUFs may remain undiagnosed and hence a better
understanding of the prevalence and causes of AUF geographically would
help in narrowing down the vast diagnostic workup needed to pin point
the aetiological agent and guide to an optimal treatment to avoid
unwanted usage of antibiotics and antimalarials [5, 10]. We study here
the most common aetiologies and clinical features of AUF in a teaching
hospital with patients hailing mostly from Rural Pondicherry and,
Villupuram, Cuddalore and Thiruvannamalai districts of Tamil Nadu.

Materials
and Methodology

The present study emphasizes on the infective aetiologies of Acute
Undifferentiated fevers with special emphasis on clinical and
demographic features among patients admitted in a teaching hospital in
Pondicherry. This study was undertaken in the Dept. of General Medicine
and required cases were taken from among the inpatients of the same
during the period of November 2015 to May 2017.

Inclusion criteria: All
adult patients (≥18 years) admitted to the hospital with fever
of less than 21 days duration, with temperature ≥38º C
upon admission and non-detection of any specific foci of infection by
history, physical examination and routine investigations.

Data entry and analysis: The
data was entered in Microsoft Excel and analysed using Epi Data
analysis V2.2.2.186 and STATA 12.0 software. The continuous variables
like age, duration of fever and ESR at 1 hour were reported as Mean
(SD) or median (Inter Quartile Range) based on distribution of data.
The categorical variables such as gender, presence of symptoms
(myalgia, jaundice, haemorrhage, conjunctival congestion, diarrhoea and
cough or dyspnoea), test results (malaria slide examination, RDT for
malaria, thyroid function test, sputum examination, dengue, scrub
typhus, leptospirosis, Widal test, blood culture, urine culture, HIV,
HCV, Hbs Ag), finding from chest X ray, USG findings and final
diagnosis of undifferentiated fever were reported as proportions. In
comparison analysis, the final diagnosis categories with less number of
patients were excluded from analysis. The association between
continuous variables [age, duration of fever and ESR at 1 hour] and the
final diagnosis of undifferentiated fever were assessed using one way
ANOVA or Kruskal Wallis test and the association between categorical
variable and the final diagnosis of undifferentiated fever were
assessed using Chi Square test or Fisher’s exact test based
the cell values. The p value of <0.05 was considered for
statistical significance.

Ethical consideration:
The ethical approval for the study was obtained from the Institute
Ethical committee of Sri Manakula Vinayagar Medical College and
Hospital, Pondicherry. All ethical principles were adhered in the study

Data collection: All
participants were briefed about the study in the language they
comprehend and their willingness to participate in the study was
obtained through informed consent form. Detailed clinical history was
obtained from the selected patients and a thorough physical examination
done for each. Blood, urine and sputum samples were taken from the
study group and sent for the following investigations accordingly:

Investigations and
methodology followed: Investigations were done as per the
clinical assessment.

Result

Out of the 270 cases of patients of the age 18 and above, the mean age
was 39.1 years. 53.7% (145) were males and 46.3% (125) were females.

The mean duration of fever at presentation to clinic was of 6.9
days.71.5% (193) of the patients complained of myalgia.10.4% (28) of
the patients with AUF in our study presented with diarrhoea.39.6% (107)
of the patients in our study presented with cough and/or dyspnoea. The
mean ESR value among the study group after 1 hour reading was 33.4 mm.

5.6% (15) cases of AUF came positive for P. vivax malaria by smear
examination and 5.2% (14) cases where also positive by Rapid Diagnostic
Test. There were no other malarial parasites found in the study
population. All cases suspected of a thyroid disorder were of euthyroid
state among the 270 cases of AUF in our study group.1 case was positive
for Acid fast bacilli, 1 for Candida species and 1 for Klebsiella
pneumonia among the 270 cases in the study group of AUF. Dengue was
found to be positive among 20% (54) of the study population. Scrub
typhus was found positive in 38.1% (103) of the study population. Widal
test was positive for 14.1% (38) patients out of the study population.

Table-1: Final diagnosis
of AUF

Final aetiology

Number

Percentage

Dengue

43

15.9

Dengue/Scrub typhus

3

1.1

Enteric fever

33

12.3

P.vivax malaria

14

5.2

Scrub typhus

103

38.1

UTI

2

0.7

Viral fever

64

23.7

Dengue/UTI

1

0.4

Enteric fever with liver abscess

1

0.4

Scrub typhus/P.vivax

1

0.4

Scrub typhus/sepsis

1

0.4

Scrub Typhus/Enteric

1

0.4

Scrub Typhus/UTI

1

0.4

Sepsis

1

0.4

Tuberculosis

1

0.4

Total

270

100

38.1% (103) of the diagnosed patients were of Scrub Typhus aetiology,
23.7% (64) of them were of miscellaneous aetiology, 15.9% (43) of the
cases were Dengue and Enteric fever accounted for 12.3% (33). [Table 1]

Discussion

The purpose of this study was to identify and compare the various
causes and clinical presentations of acute undifferentiated fever in a
teaching hospital in Pondicherry. Majority of the patients were in the
middle age group (mean age of 39.1) at risk for likely exposure to
environmental pathogens. Mean duration of fever was 6.9 days and
myalgia was the most common presenting feature with 71.5% patients
followed by cough/dyspnoea with 39.6% and diarrhoea 10.4%. The age
group between 20 to 50 years is the economically productive period
during which they have high chance of having contact with contaminated
environment. The predominance in males is likely to be due to more
chance of exposure to organisms due to their nature of work. Lower
utilization of health care delivery facilities by females due to
socio-cultural reasons could be another reason.

Males were affected twice as that of females. This may be due to their
easy exposure to mosquitoes and mites because of their outdoor
activities.

The study revealed the heavy burden of tropical infections such as
dengue, enteric fever, scrub typhus and malaria. Previous studies in
Northern and Southern parts of the country have shown the similar
results [3, 11, 12, 13]. A similar study conducted by Singh R et al.,
from the region of Uttarakhand also showed that dengue, malaria,
typhoid and enteric fever are the most common aetiological agents of
acute febrile illness [14].

Major causes of AUF identified were Scrub Typhus, Dengue fever, Enteric
fever and undiagnosed fever taken to be that of viral aetiology.

In India infectious disease remains the main cause of fever [15]. In a
cohort study by Abrahamsen et al., from Southern India, bacterial
infections (38%) and TB (19%) were the most common aetiological agents
of fever [16]. Another study from east India reported that TB (53%),
neoplasms (17%) and collagen vascular disorders (11%) were the dominant
causes.8But our study diagnosed only 1 case of Tuberculosis which is
partly due to a dedicated Tuberculosis and chest department functioning
separately in our hospital.

In our study, Scrub Typhus was at the top of the list, constituting
38.1% of the infectious causes. In our study, we could establish the
diagnosis in 76.3% of the cases.

Dengue, malaria, scrub typhus, enteric fever and leptospirosis have
been identified as major causes of AUFI in Thailand, Malaysia and Nepal
[17, 18, 19, 20]. Various studies conducted particularly in South India
by Chrispal et al., Gopalakrishnan et al., and Kashinkunti et al., have
also showed similar results [22, 22, 23].

In the miscellaneous group of our study, no definite cause was found in
23.7 %(64) and was presumed to be of viral origin. Further studies are
needed to identify the causes of fever in the miscellaneous group.

Second highest frequencies of diagnosed AUF were that of Dengue Fever,
being diagnosed in 20% (54) of our sampled population. These results
underline the importance of awareness by health centre staff to be able
to distinguish viral infections and be aware of their possible
complications. The proportion of dengue fever among all fever cases has
been estimated to be 14% in a population-based study in rural South
India and 48% in a hospital based study in urban North India [24, 25].

Bleeding diathesis is a known feature of Dengue and Scrub typhus
because of low platelet count and leakage from blood vessels. Bone
marrow suppression, Immune mediated clearance, spontaneous aggregation
of platelets to virus infected endothelium-all may be responsible for
such thrombocytopenia. In our study, we found only 1 patient with
bleeding episodes in the form of gum bleeding and/or melena who was
diagnosed with Dengue. Therewere no death within our study population
during the period of study.

Leptospirosis and Salmonella infections have been implicated in
causation of one-third and one-tenth of all fever cases in 2 different
studies [26, 27]. In our study group 12.3% (33) of the patients were
diagnosed to have Enteric fever by Widal test and 1 case of
Lepstospirosis by serology.

Despite AUF being common, the studies on its epidemiology remain
limited. Recently, the public health system in India has initiated a
more systematic integrated disease surveillance program (IDSP), which
aims to compute the burden of infectious diseases, including AUFs, in a
more comprehensive manner [28].

Malaria were less frequent in this study (5.2%). All of them were ofP.
vivaxaetiology. UTI was a frequent diagnosis with 7 cases of E. coli, 1
case of Enterococci and 1 case of Staphylococci.

Mixed infection with more than one aetiological agent can result in an
illness with overlapping symptoms, resulting in a situation where the
diagnosis and management of such a patient could be challenging for the
treating physician [29, 30, 31, 32, 33]. In our study there were 3
cases of Scrub Typhus with Dengue Fever and other isolated cases of
Scrub Typhus with Malaria, Enteric Fever, UTI and Sepsis. There was
also a case of Dengue with UTI. These cases were excluded from further
analysis as they may show compounding features due to their mixed
nature of disease. Symptoms of one disease may mimic with other disease
which are also prevalent in this area. So, patients presenting with
acute febrile illness should not be presumed to be suffering from
single infection alone. The clinician should investigate thoroughly to
look for other causes of fever.

In our study, the HIV infection was detected in only 1 patient despite
the relatively high-risk study population (i.e., adults with febrile
illness). This is important information given the general concern in
about rising HIV infection rates in our country [34].

In spite of methodological difficulties, there was a large number of
AUF that went undiagnosed. Rapid advances in molecular biology research
and the avail¬ability of high throughput sequencers are a
promising tool to reduce the number of undiagnosed AUF cases in the
future. These advances may enable the identifi¬cation of occult
infections and previously unknown pathogens. This new method does not
rely on a knowledge of the pathogens being sought but provides bulk
sequenc¬ing of any nucleic acid present in the sample [35].
This technology to diagnose AUF should be further explored.

We did not intend to perform an exhaustive search for all potential
causes of fever among our febrile adults. Our main purpose was to
describe the burden of some of the most likely pathogens, and to use
this data as a foundation for further more focused research. Our
results may underestimate the true burden for several reasons. First,
hospital-based studies tend to underestimate disease incidence [36].
While this approach facilitates use of laboratory services,
hospital-based surveillance captures only the most severe illnesses in
people who have access to hospital care. Second, antibiotics can be
purchased without prescription in India. Undoubtedly, antibiotic use
reduced the ability to isolate pathogens from blood cultures.

This study demonstrates the usefulness of expanding microbiologic
capacity in the developing world and the value of laboratory-based
studies in sentinel institutions. Such studies provide a snapshot of
important infections and can be periodically repeated for surveillance
purposes. We have to be on the guard for emerging and re-emerging
infections such as Dengue and Scrub Typhus.

Our study has a few limitations. We have focused on hospitalized adults
(i.e., the most severely ill patients), our study findings should not
be generalized to the acute febrile illness subtypes seen in
outpatients or in the community. Patients were followed only until a
diagnosis was confirmed or if patient recovered within the study period
in case of miscellaneous fevers. Any patient who crossed over to FUO
were not followed up. Treatment and recovery of the cases were not
followed up after the diagnosis was made. Our results cannot be applied
to infants and children. Several other infections that have been
described to cause fever in the area were not systematically pursued.
Important among this group are Japanese encephalitis, Hepatitis E,
Epstein-Barr-virus, Hepatitis A, Hepatitis E, and Coxsackie virus,
Influenza and other bacterial infections such as Q-fever,
Brucellosisand Melioidosis

Conclusion

In conclusion, despite AUF being common, studies regarding its
epidemiology are limited. In our study, serology is the most common
diagnostic tool and the most prevalent aetiologies of AUF are Scrub
Typhus, Dengue and Enteric fever.

Our data showed that the etiologic spectrum of acute undifferentiated
fever was widely distributed in our region. Scrub typhus was the major
cause of acute undifferentiated fever next to Dengue and Enteric fever.
There were a bulk of cases which were not diagnosed and put under
miscellaneous aetiology of fever, this made the second largest group in
our study next to the Scrub Typhus group. This bulk of cases are a
reflection of how much more we need to improve our clinical and
diagnostic methodologies in order to make a prompt and accurate
diagnosis in spite of all the currently available methods.

The clinical evaluation of the subjects recruited for this study has
not revealed any predictor symptoms or specific risk factors to
differentiate between the different causes of AUF.The lack of a widely
agreed upon definition of AUF makes compari¬son of patients
with AUF between regions and countries difficult. Further studies need
to be conducted using a standard definition of AUF by evaluating
patients clinically and serologically for detecting infectious diseases.

What this study
contributes to present scenario?
Our data showed that the etiologic spectrum of acute undifferentiated
fever is widely distributed in our region. Scrub typhus was the major
cause of acute undifferentiated fever next to Dengue and Enteric fever.
This can guide us to concentrate our diagnostic process and treatment
to focus on the more likely aetiologies from this region. There were a
bulk of cases which were not diagnosed and put under miscellaneous
aetiology of fever, this made the second largest group in our study
next to the Scrub Typhus group. This bulk of cases are a reflection of
how much more we need to improve our clinical and diagnostic
methodologies in order to make a prompt and accurate diagnosis in spite
of all the currently available methods.

3. Joshi R, Colford Jr JM, Reingold AL, Kalantri S. Nonmalarial acute
undifferentiated fever in a rural hospital in central India: diagnostic
uncertainty and overtreatment with antimalarial agents. The American
journal of tropical medicine and hygiene. 2008 Mar 1;78(3):393-9.
4. Crump JA. Time for a comprehensive approach to the syndrome of fever
in the tropics. Transactions of the Royal Society of Tropical Medicine
and Hygiene. 2014;108(2):61-2

36. Pappachan MJ, Sheela M, Aravindan KP. Relation of rainfall pattern
and epidemic leptospirosis in the Indian state of Kerala. Journal of
Epidemiology & Community Health. 2004 Dec 1;58(12):1054-. [PubMed]How to cite this article?